GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation
GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation
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DOI：
10.1097/mib.0000000000000847
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发表时间：
2016-09-01
影响因子：
4.9
通讯作者：
Frederiksen, Klaus S.
中科院分区：
文献类型：
--
作者：
Bang-Berthelsen, Claus H.;Holm, Thomas L.;Frederiksen, Klaus S.
背景资料：胰高血糖素样肽1（GLP-1）/GLP-1 R信号传导的有益作用最近已被描述在疾病中，其中低度炎症是常见现象。我们研究了GLP-1受体丰富表达的Brunner's腺和十二指肠中GLP-1的作用，以及GLP-1对结肠inflammation.Methods的影响：对来自GLP-1 R敲除小鼠和野生型小鼠Brunner's腺的RNA进行全转录组分析。通过野生型小鼠的定量逆转录聚合酶链反应验证了阵列结果，并与炎症性肠病（IBD）患者和对照组的样本进行了比较。此外，我们进行了详细的调查外源性利拉鲁肽剂量的影响，在T细胞驱动的过继转移（AdTr）结肠炎小鼠model.Results：分析的Brunner的腺转录组的GLP-1 R敲除和野生型小鼠确定了722差异表达的基因。GLP-1给药后上调的转录物包括IL-33、趋化因子配体20（CCL 20）和粘蛋白5 b。IBD患者和对照组的活检以及AdTr模型的数据显示结肠中GLP-1 R、CCL 20和IL-33的表达失调。发现结肠炎小鼠的GLP-1循环水平升高。最后，结肠细胞因子水平和AdTr模型的疾病评分表明利拉鲁肽给药的动物结肠炎症水平降低。结论：我们证明IL-33，GLP-1 R和CCL 20在人类IBD中失调，并且用0.6 mg/kg利拉鲁肽预防性治疗可改善AdTr结肠炎的疾病。此外，GLP-1受体激动剂上调小鼠Brunner腺中的IL-33、粘蛋白5 b和CCL 20。总之，我们的数据表明GLP-1受体激动剂影响肠道近端和远端部分的肠道稳态。
Background: Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well as GLP-1 effect on colonic inflammation.Methods: RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from inflammatory bowel disease (IBD) patients and controls. In addition, we performed a detailed investigation of the effects of exogenous liraglutide dosing in a T-cell driven adoptive transfer (AdTr) colitis mouse model.Results: Analyses of the Brunner's gland transcriptomes of GLP-1R knockout and wild-type mice identified 722 differentially expressed genes. Upregulated transcripts after GLP-1 dosing included IL-33, chemokine ligand 20 (CCL20), and mucin 5b. Biopsies from IBD patients and controls, as well as data from the AdTr model, showed deregulated expression of GLP-1R, CCL20, and IL-33 in colon. Circulating levels of GLP-1 were found to be increased in mice with colitis. Finally, the colonic cytokine levels and disease scores of the AdTr model indicated reduced levels of colonic inflammation in liraglutide-dosed animals.Conclusions: We demonstrate that IL-33, GLP-1R, and CCL20 are deregulated in human IBD, and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts of the gut.